Alcohol abuse represents a major clinical condition in the Unites States and worldwide. Despite the prevalence of alcohol dependence and the well-known adverse effects of chronic alcohol exposure, the neurobiological mechanisms mediating alcohol's effects in the brain are still not fully understood. The challenge of current and future studies is to understand the neurobiological changes that influence tolerance and dependence in motivational systems that lead to chronic drinking. The central amygdala (CeA) is a major component of the brain involved in the motivational effects of drugs of abuse and alcohol in particular (Alheid and Heimer, 1988). The inhibitory neurotransmitter GABA is a key element of the CeA circuitry and is a critical component of the behavioral effects of acute and chronic ethanol consumption (Hyytia &Koob, 1995;Roberts et al., 1996). To date, studies in the CeA have predominantly focused on alterations in the presynaptic GABA system (Roberto et al., 2003, 2004). Importantly, no studies have examined a specific form of GABAA receptor signaling characterized by persistent inhibitory currents mediated by GABAA receptors with a distinct subunit composition. Denoted tonic inhibition, this form of GABAA receptor signaling has been shown to have high sensitivity to ethanol (Wallner et al., 2003) and has been implicated in the effects of alcohol in several brain regions (Wei et al., 2004;Liang et al., 2007;Jia et al., 2008). However, no studies have been performed on this type of GABAA receptor signaling in the CeA. Therefore, the goal of this proposal is to characterize tonic GABAA receptor signaling in the CeA and to investigate the effects of acute and chronic ethanol exposure on this signaling. Applying electrophysiological and molecular techniques to elucidate alterations in tonic GABAA receptor expression and function in the CeA will provide important information as to the cellular changes that contribute to the transition from recreational alcohol consumption to dependence. This information could contribute to improved treatment of alcohol dependence and/or the development of potential therapeutics. PUBLIC HEALTH RELEVANCE: This proposal utilizes electrophysiological and molecular techniques to characterize a novel cellular neuroadaptation to ethanol exposure in the CeA. The overarching hypothesis is that changes in tonic GABAA receptor signaling in the CeA are a major contributing factor in the development of alcohol dependence. The results of these studies will provide important information as to one of the underlying mechanisms related to the development of alcohol dependence and could contribute to improved treatment of alcohol dependence and/or the development of potential therapeutics.